Year: 2015
Type: article
Abstract: Meiosis-activating sterols (MAS) are substrates of SC4MOL and NSDHL in the cholesterol pathway and are important for normal organismal development. Oncogenic transformation by epidermal growth factor receptor (EGFR) or RAS increases the demand for cholesterol, suggesting a possibility for metabolic interference. To test this idea in vivo, we ablated Nsdhl in adult keratinocytes expressing KRAS(G12D). Strikingly, Nsdhl inactivation antagonized the growth of skin tumors while having little effect on normal skin. Loss of Nsdhl induced the expression of ATP-binding cassette (ABC) transporters ABCA1 and ABCG1, reduced the expression of low-density lipoprotein receptor (LDLR), decreased intracellular cholesterol, and was dependent on the liver X receptor (LXR) α. Importantly, EGFR signaling opposed LXRα effects on cholesterol homeostasis, whereas an EGFR inhibitor synergized with LXRα agonists in killing cancer cells. Inhibition of SC4MOL or NSDHL, or activation of LXRα by sterol metabolites, can be an effective strategy against carcinomas with activated EGFR-KRAS signaling.
Source: Cell Reports
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,620
Awards: G1062996462, Molecular Studies of X-Linked Chondrodysplasia Punctata, G156276794, G1948895391, Targeting Sterol Gene SC4MOL and EGFR as Synergistic Anti-Cancer Strategy, Regulation of EGFR by SC4MOL- and NSDHL-Dependent Trafficking, G3771026464, Cas Protein Regulation of EMT in Cancer, G4496438841, G6408618350, HEI C AND MORPHOGENESIS AND SIGNALING, G921727105
OpenAlex ID: W1809717564